Electromagnetic Wireless Remote Control of Reprogramming Immune Dysfunction via N‐Doped Carbon Dots–Mesoporous Silica‐Mediated Cuproptosis and Dendritic Cell Retention
Hui‐Wen Lien, Yun‐Yen Kuo, Yun‐Hsuan Chang, Thi My Hue Huynh, Bhanu Nirosha Yalamandala, Tung Chin Li, Hoi‐Man Iao, Wulin Pan, Alan Yueh‐Luen Lee, Wen‐Hsuan Chiang, Shang‐Hsiu Hu
Abstract
Dendritic cells (DCs) are key initiators of antitumor immune responses. However, dendritic cells frequently exhibit compromised antigen-presenting capabilities and adopt an immunoregulatory or tolerogenic phenotype, contributing to immune suppression in tumor microenvironment, severely limiting their efficacy. To overcome this, a pH-responsive lung-metastasis-targeted wirelessly charging-boosted dual-catalyst nanoplatform composed of tumor-penetrating solid lipids/polymer-coated N-doped carbon dots/mesoporous silica nanoparticles (CMS), loaded with cuproptosis-inducing agents (elesclomol-copper, EsCu) is developed for initiating a self-cascade immune response and dendritic cell retention. Upon exposure to alternating magnetic fields (AMFs), N-doped carbon dots can generate the currents and enhance cuproptosis through mechanisms consistent with Kelvin's force laws, boosting catalytic activity. Intravenously injected CMS selectively accumulates at metastatic tumor sites through pH-triggered charge switching, while the positive charge also promotes the release of cell-cell interactions. At tumor site, Es and Cu are released in response to intracellular conditions and AMF stimulation, inducing cuproptosis in cancer cells and disrupting immune evasion. This cytotoxicity is paired with in situ antigen release, which CMS carriers deliver to reprogram DCs, initiating sustained immune activation. When combined with immune checkpoint blockade (anti-PD-1), the CMS system effectively suppresses lung metastases and extends survival beyond 60 days.